ADMET and DMPK最新文献

Background and purpose: Treatment of chronic myeloid leukaemia includes targeted therapy with tyrosine kinase inhibitors (TKIs): imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib. This review aims to prove that electrochemical sensors provide a reliable alternative to the conventional analytical methods for highly sensitive and cost-effective assay of TKIs in pharmaceutical formulations and biofluids. These platforms have significant advantages in fast detection and portability because they could be designed as miniaturized hand-held devices suitable for real-time point-of-care analysis, providing quick results for enabling personalized therapeutic drug monitoring.

Experimental approach: The paper covers recent developments in substrate materials, various electrode designs, the advantages, and limitations of sensors for TKIs, encompassing both basic and applied research.

Key results: This is a pioneering study that provides a general review on emerging trends, technologies, and practical applications of electrochemical sensors for TKIs analysis. The article provides researchers with a clear introduction and concise guide to the design and application of electrochemical sensors in the clinical analysis of TKIs.

Conclusion: The review is intended to serve as a valuable resource for researchers in navigating the latest developments in TKIs' electrochemical sensing platforms. The fast response, high sensitivities and satisfactory recoveries obtained in blood serum and urine samples show the potential for application of the proposed electroanalytical systems in clinical analysis and optimization of chemotherapeutic treatments.

Introduction and background: The world has witnessed several outbreaks, emergence and re-emergence of infectious diseases throughout the 21^st century as a result of climate change, urbanization and migration. Several infectious diseases caused by pathogens such as SARS-CoV-2, Ebola, Zika, Dengue, Marburg viruses, Mycobacterium tuberculosis, etc. have caused a devastating impact on lives and livelihoods around the world. To counter these diseases, medical experts rely on conventional techniques, which include microscopy and serological testing. However, these conventional methods are hindered by several trade-offs, including high cost, longer processing times, low sensitivity, and a likelihood of false positive results. Biomedical sensors have gained momentum in clinical diagnostics due to their low cost, portability, and sensitivity, among other advantages. To improve their performance, scientists have incorporated nanomaterials. Other techniques used to enhance the performance of nanobiosensors include multiplex testing, point-of-care testing (POCT), and smart sensing.

Methodology: Thus, in this review, we present a comprehensive overview of the state-of-the-art nanobiosensors for detecting infectious diseases. The review covers key topics that are centred around the application of nanotechnology in biosensing, multiplex testing, POCT and smart nano-enhanced biosensors.

Findings: The findings of this review highlighted the advantages of biosensors over conventional approaches, with a limit of detection ranging from nanomolar to attomolar concentrations and a time response ranging from 1 to 3 hours.

Conclusion: Despite the prospect of nanobiosensors, several limitations exist, including complexity, extensive processing time, and others. Moreover, the integration of smart technologies in nanobiosensors can offer several benefits, including high accuracy and faster detection and prediction.

Background: Microfluidic nanoprecipitation followed by freeze-drying would yield uniformly sized, stable nanoparticles by preserving their physicochemical property without compromising therapeutic performance. The isoniazid (INH)-loaded poly-ε-caprolactone (PCL) nanoparticles could be developed using a microfluidic technique for the management of tuberculosis.

Experimental approach: The INH-loaded nanoparticles were fabricated via a microreactor-assisted nanoprecipitation method and optimization using a design of experiments factorial design approach. The resulting INH-PCL nanoformulation was characterized for particle size, polydispersity index (PDI), zeta potential (surface charge), Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis and field emission scanning electron microscope.

Key results: The optimized nanoparticles exhibited an average particle size (248.4 ± 5.372 nm) and high encapsulation efficiency (82.26 ± 4.36 %). Thermal and spectroscopic analyses confirmed the absence of drug-polymer interactions, ensuring formulation integrity; stability studies under accelerated conditions demonstrated negligible changes in particle size, PDI, and zeta potential over the period of 6 months, indicating robust colloidal stability. A scanning electron microscopy study revealed rod-shaped nanoparticles with smooth surfaces. Lyophilization (freeze-drying) enhanced long-term stability, yielding a readily re-dispersible powder (reconstitution index ~1.066). Following diffusion-controlled kinetics, in vitro drug release studies in phosphate buffer saline (pH 7.4) showed sustained drug release (92.45 % cumulative release over 48 h).

Conclusion: Our results confirm that the INH-loaded PCL nanoformulation combines excellent stability, high drug-loading capacity, and sustained release, key attributes of effective tuberculosis therapy.

Background and purpose: The effective transport of an active pharmaceutical ingredient across various membrane systems is critical for enhancing its bioavailability, especially in formulations involving solubilizing agents. This study aims to investigate the permeability differences of carvedilol (CAR) between lipophilic and size-exclusion membranes in the presence of hydroxypropyl-beta-cyclodextrin (HP-β-CD) using in vitro side-by-side diffusion cell assays.

Experimental approach: Solubility and permeability assays confirmed that HP-β-CD significantly enhanced the solubility of CAR, while simultaneously decreasing its permeability, indicating an interplay between the two parameters.

Key results: A mathematical model based on Fick's first law of diffusion was developed to describe drug transport across the UWL, and generally through the UWL-membrane system, with a particular focus on the role of solubilizing agents.

Conclusion: Results from both the UWL and membrane limited transport conditions demonstrated that the supersaturation ratio (SSR, defined as the ratio of the drug concentration present in solution to its thermodynamic solubility measured in exactly the same media) between donor and acceptor compartments is the real driving force of the transport, when the complexing agent and the drug- HP-β-CD complex does not penetrate the membrane or the permeation of the solubilizing additive through the membrane is relatively slow, so it does not affect the transport of the API substantially.

In the present work, SnO₂ nanostructures were synthesized and a sensitive voltammetric sensor on a glassy carbon electrode (GCE) was constructed to estimate morphine (MP) in the presence of diclofenac (DLF).

Background and purpose: Because diclofenac (DLF) is an NSAID, its administration can reduce postoperative morphine (MP) requirements in adults; for example, standard DLF dosing has been shown to decrease MP use after abdominal surgery. Hence, devising a simple, cost-effective, and swift assay for these compounds in biological and pharmaceutical specimens is indispensable.

Experimental approach: SnO₂ nanostructures were synthesized, and a sensitive voltammetric sensor on a glassy carbon electrode (GCE) was constructed to estimate MP in the presence of DLF. Cyclic voltammetry was employed to evaluate the electrochemical response of the SnO2 nanostructures/GCE towards MP.

Key results: The SnO₂ nanostructures exhibited a significant effect on the electrochemical reaction of the electrode toward the MP oxidation. The SnO₂ nanostructures/GCE further exhibited a more sensitive detection platform for MP determination with a limit of detection of 0.006 μM using differential pulse voltammetry in a linear range of 0.01 to 340.0 μM.

Conclusion: The SnO₂ nanostructures/GCE exhibited extremely high electrochemical activities towards the simultaneous oxidation of MP and DLF. Moreover, the SnO₂ nanostructures/GCE provided reproducible and stable responses for MP quantitation. The platform prepared showed successful performance for MP and DLF determination in real samples. SnO₂ nanostructures exhibited a significant effect on the electrochemical reaction of the electrode toward the MP oxidation. The SnO₂ nanostructures/GCE further exhibited a more sensitive detection platform for MP determination with a limit of detection of 0.006 μM using differential pulse voltammetry in a linear range of 0.01 to 340.0 μM. Additionally, the SnO₂ nanostructures/GCE exhibited extremely high electrochemical activities towards the simultaneous oxidation of MP and DLF. Moreover, the SnO₂ nanostructures/GCE provided reproducible and stable responses for MP quantitation. The platform prepared showed successful performance for MP and DLF determination in real samples.

Background and purpose: It is generally known that the majority of disorders exhibit symptoms to some degree when the quantities of two crucial substances, epinephrine and folic acid, are low or high. These two chemicals' composition variations may be tracked and utilized to identify conditions such as myocardial infarction, Parkinson's disease, and mental disorders.

Experimental approach: Using a solvothermal technique, we propose the synthesis of a novel MIL-101 (Fe)-NH₂ metal-organic framework/graphene oxide nanocomposite (MOF/GO nanocomposite). The produced nanocomposite's morphology was examined using field-emission scanning electron microscopy. A straightforward, quick, and sensitive electrochemical sensing platform for epinephrine detection was then created by drop-casting the produced MOF/GO nanocomposite onto the screen-printed electrode (SPE).

Key results: Compared to unmodified SPE, cyclic voltammetry revealed that the MOF/GO/SPE considerably enhanced the epinephrine oxidation process, exhibiting a greater detection current at a lower over-potential. The synergistic combination of MOF and GO sheets may cause this discovery. With a low detection limit of 0.07 μM, the MOF/GO/SPE sensor's linear response for voltammetric measurements of epinephrine was found to be between 0.2 and 500.0 μM. A modified electrode was also utilized to measure folic acid and epinephrine simultaneously.

Conclusion: Lastly, the modified SPE effectively demonstrates its high accuracy in identifying folic acid and epinephrine in biological and pharmaceutical samples.

Background and purpose: Multifunctional hybrid nanoparticles garner heightened interest for prospective biomedical applications, including medical imaging and medication administration, owing to their synergistic benefits of constituent components. Therefore, we demonstrated an optimized protocol for synthesizing magnetofluorescent nanohybrids comprising fluorescent carbon dots with magnetic nanoparticles.

Experimental approach: Carbon dot-coated iron oxide nanoparticles (CDs@Fe₂O₃) were synthesized with varying citric acid concentrations by a one-pot hydrothermal synthesis method for the development of a low-cost and biocompatible contrast agent (CA) for enhanced multimodal imaging (fluorescent and T ₁ and T ₂ weighted magnetic resonance imaging (MRI)) to replace the conventional CAs.

Key results: The physicochemical characterization of the synthesized CDs@Fe₂O₃ revealed that 3 g of citric acid used for the synthesis of nanoparticles, keeping Fe(II) and Fe(III) ratio 1:2 provides higher stability of -78 mV zeta potential, saturation magnetization of 24 emu/g, with a hydrodynamic diameter of 68 nm. Carbon coating affects surface spins on Fe₂O₃, resulting in fewer surface-based relaxation centres, making T ₁ relaxation relatively more prominent. Furthermore, the surface-engineered iron oxide NPs are efficient in producing both T ₁ and T ₂ weighted MRI as well as fluorescence-based imaging. The molar relaxivity and molar radiant efficiency derived from phantom studies demonstrate their effectiveness in multimodal medical imaging. The cytotoxicity assay, haemolysis assay, haematology, and histopathology studies show that the optimized CDs@Fe₂O₃ are biocompatible, haemocompatible, and negligibly toxic.

Conclusion: We can conclude the significant potency of CDs@Fe₂O₃ for multimodal diagnosis.

Background and purpose: Multidrug-resistant tuberculosis (MDR-TB) remains a significant challenge in tuberculosis (TB) treatment, driven by simultaneous mutations in the rpoB and katG genes that confer resistance to rifampicin and isoniazid. While many molecular diagnostic tools focus on rpoB, the katG gene is often overlooked despite its critical role in confirming MDR-TB. This study aims to develop a CRISPR/Cas9-based electrochemical biosensor for the rapid and selective detection of katG mutation.

Experimental approach: A guide RNA (gRNA) specific to the mutation site on katG gene was designed using the Benchling CRISPR tool, considering on-target and off-target scores, specificity, and cleavage sites within the Mycobacterium tuberculosis genome. The selected gRNA achieved the highest on-target score of 61.2 and an off-target score of 49.0 at cut position 2928, with a PAM sequence of AGG. Its cleavage efficiency was validated experimentally using an electrochemical biosensing platform incorporating a gold-modified screen-printed carbon electrode (SPCE/Au). Redox response enhancement by [Fe(CN₆)]^3-/4- confirmed the improved performance of the electrode.

Key results: The biosensor system detects the target DNA through hybridization with DNA probe-Fc, forming double-stranded DNA (dsDNA) that is recognized and cleaved by the Cas9/gRNA complex. This cleavage significantly reduces the ferrocene oxidation signal, indicating the presence of a katG mutation. Non-mutated target DNA produces a nondetectable ferrocene signal, suggesting that the Cas9 enzyme may remain bound to the electrode without cleavage. The CRISPR/Cas9 electrochemical biosensor demonstrated a low detection limit of 7.5530 aM and a detection range of 10¹ to 10⁶ aM.

Conclusion: The CRISPR/Cas9-based electrochemical biosensor exhibits high sensitivity and specificity for the detection katG mutation, offering a promising platform for rapid MDR-TB diagnostics.

Background and purpose: Mitochondrial DNA (mtDNA) mutations can impair oxidative phosphorylation and ATP production, potentially contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to investigate the relationship between mtDNA mutations and ATP levels in blood and urine samples from T2DM patients.

Experimental approach: Samples from 60 patients (30 with T2DM + mitochondrial disease [MD] phenotype and 30 with T2DM alone) were analysed. mtDNA mutations A3243G and G9053A were detected using qPCR with dual-labeled probes (FAM for mutant, HEX for wild type) based on Cq comparisons. ATP concentrations were measured using a screen-printed carbon electrode (SPCE)-based electrochemical aptasensor.

Key results: The A3243G mutation was more frequent and had higher heteroplasmy levels than G9053A, particularly in the T2DM + MD group. Although no statistically significant differences in ATP levels were observed between groups, descriptive ranges showed lower ATP concentrations in the T2DM + MD group (314 to 919 μM) compared to the T2DM group (746 to 1130 μM), both below the physiological range (1.500 to 1.900 μM). A similar pattern was found for A3243G mutation levels, while G9053A levels overlapped between groups. Two-way ANOVA showed a significant association between mutation presence and reduced ATP levels.

Conclusion: The A3243G mutation may be more directly associated with mitochondrial ATP depletion in T2DM, while the role of G9053A remains inconclusive. This study highlights the potential of combining molecular and electrochemical tools to assess mitochondrial contributions in diabetes.

Background and purpose: Warfarin is a widely prescribed oral anticoagulant for the prevention and treatment of thromboembolic events, frequently used in patients with atrial fibrillation. However, its effectiveness is often challenged by a narrow therapeutic range and significant inter-patient variability in dosage requirements and treatment responses. Drug interactions remain a critical concern, as they heighten the risk of supratherapeutic anticoagulation. Reports of interactions between warfarin and mango have documented cases of elevated international normalized ratio (INR) following mango consumption, although the underlying molecular mechanisms remain unclear.

Experimental approach: This study investigates the molecular basis of the warfarin-mango interaction using proton nuclear magnetic resonance (¹H-NMR)-based metabolomics. In a pre-post design study, plasma samples were collected from patients on long-term warfarin therapy (>6 months) who exhibited supratherapeutic INR levels after consuming mango. After a two-week discontinuation of mango consumption, additional plasma samples were collected once INR levels returned to the therapeutic range.

Key results and conclusion: This is the first study to utilize ¹H-NMR metabolomics to explore warfarin-mango interactions, integrating clinical observations with metabolic insights. Findings suggest that a reduction in glycerol 3-phosphate may impair glycolysis, disrupting platelet activation and contributing to the elevated INR levels observed in all patients. These results underscore the potential for ¹H-NMR metabolomics to elucidate drug-food interactions, advancing personalized anticoagulant management and improving patient safety.